Nervous system injuries affect millions of people every year. As a result of this high incidence of neurological injuries, neuronal regeneration and repair is becoming a rapidly growing field dedicated to the discovery of new ways to recover nerve functionality after injury. The nervous system is divided into two parts: the central nervous system (CNS), which consists of the brain and spinal cord, and the peripheral nervous system (PNS), which consists of cranial and spinal nerves along with their associated ganglia. A brain injury or brain damage is the destruction or degeneration of brain cells in the brain of a living organism. Brain injuries can be classified along several dimensions. Primary and secondary brain injuries are ways to classify the injury processes that occur in brain injury.
Post traumatic regeneration of the brain and spinal cord is a major unsolved medical problem because the brain and spinal cord are not able to regenerate like the peripheral nervous system. While peripheral axons regenerate in patients after nerve injury, brain and spinal cord axons fail to regenerate due to glial scar formation and the inhibitory action of chondroitin sulphate proteoglycans (CSPGs) in the scar. In addition, those factors that promote peripheral nerve regeneration, for instance nerve growth factor, NGF, fail to improve regeneration in the brain and spinal cord. The central nervous system and peripheral nervous system are very different in their reactions to drug treatment and regeneration ability.
Identifying molecular mechanisms guiding neuronal development has been a great challenge. Inhibition of chondroitin sulphate proteoglycans (CSPGs) as a mechanism to enhance neuronal growth has been of considerable interest. CSPGs have been implicated in inhibiting regeneration of axons and dendrites following CNS trauma (Silver and Miller, 2004). CSPGs are also known to be part of the glial scar that forms post-injury, acting as a barrier to prevent axon extension and regrowth. Levels of versican, neurocan, brevican and phosphacan (those CSPGs measured) have all been found to be upregulated after spinal cord injury (Jones et al., 2003).
WO2004/103299 discloses a method of improving functional recovery following a central nervous system contusion injury. The disclosed invention is directed to a method of utilizing chondroitinase (chondroitin sulfate degrading enzyme) to promote autonomic neurological functional recovery following injury in or to the spinal cord. Compositions useful in the method include acceptable formulations of chondroitinase. The method includes administering a therapeutically effective amount of glycosaminoglycan degrading enzyme. The glycosaminoglycan degrading enzyme may be dermatan sulfate or chondroitin sulfate degrading enzymes. The functional recovery may include autonomic functions, sensory functions, motor functions or the like.
WO2005/087920 relates to recombinant and modified chondroitinase ABC I, their production and their uses. The disclosed chondroitinase ABC I enzymes are useful for a variety of purposes, including therapeutic methods such as promoting nerve regeneration, promoting stroke recovery, treating spinal cord injury, treating epithelial disease, treating infections and treating cancer.
Other approaches to CSPG inhibition have focused on the use of molecules/agents that inhibit the interaction of CSPGs with its receptor RPTPσ. WO2011/022462 discloses the use of soluble fragments of RPTPs that bind CSPGs, thus acting as competitive inhibitors to prevent the CSPGs from binding RPTPs on the neuron. The neural cell can be associated with an injury or neurodegenerative condition. WO2012/112953 discloses methods for contacting a neuron with an agent that binds RPTPσ, to thereby induce neuronal outgrowth of the neuron. The agent may induce clustering of RPTPσ and/or inhibit binding of CSPGs to RPTPσ. Examples of suitable agents are heparan sulfate proteoglycan, heparan sulfate, heparan sulfate oligosaccharides, or heparin oligosaccharides.
For nervous system injuries there are substantial patient populations with significant unmet needs, for which novel treatment options are desperately required. There is currently no treatment for recovering human nerve function after injury to the central nervous system. Secondary injury mechanisms have, so far, been predominantly targeted through the use of neuroprotective treatments. However, the compounds and approaches, which have been tested in clinical trials thus far, have disappointingly failed to demonstrate clear efficacy. Consequently, the use of neuroprotective strategies, as the primary treatment option for central nervous system injuries remains in doubt and hence novel approaches are required. Finding out mechanisms and means to promote nerve regeneration is important also clinically, as it is part of the pathogenesis of many diseases. In the hunt for neurostimulatory agents that promote nerve regeneration, well-defined models and analysis methods are required.